6th January 1998, School of Pharmacy, University of London

Professor Sandy Florence welcomed around seventy delegates to the
4th UKICRS National Meeting which despite severe storms off the south
west coast, gales preventing ferry sailings from Ireland and a snow
fall in the Midlands took place in almost balmy weather conditions in
the capital. Professor Clive Wilson, chairman of UKICRS delivered the
opening address, outlining the broad aims of the society to link
academia and industry, to provide interesting scientific meetings and
funds for young scientists to attend conferences in the UK and
abroad. An important goal, achieved in 1997, was the linking of
Ireland to UKCRS to form a new UK-Ireland local chapter. Dr Anne
Brindley, the meeting organiser, then thanked committee members,
Peter Scholes, Hiep Huatan and Saghir Akhtar for assistance in
particular and acknowledged the generous sponsorship of Astra
Charnwood, 3M Healthcare, Pfizer Central Research, Jago Pharma AG,
Polymer Laboratories, Faulding Pharmaceuticals and Bristol Myers
Squib.

Dr John Devane, from Elan Pharmaceutical Technologies opened the
scientific proceedings with a talk on Continuous versus Discontinuous
Therapy : Drug Delivery and Therapeutic Issues. The central tenet
settled on the growing recognition, through the study of
chronotherapeutics, that variable or mixed drug exposure was optimal.
Intensive study of natural biological patterns had revealed strong
links over a 24 hour period with the pattern of activity and
associated symptomatology of the diseased state. The combination of
chronotherapeutics with chronopharmacokinetics (variation of drug
kinetics with the time of day it is administered) and
chronopharmacodynamics (variation of biological responses with the
time of day) has resulted in the ability to define optimal drug
exposure/time profiles. This in turn has created major challenges but
also opportunities for drug delivery to meet new and complex
therapeutic regimens. One intriguing response involves the
integration of biosensor technology and feedback drug delivery
technology to produce individualised 'smart pills' .

Dr Rob Horne, senior lecturer in Health Psychology and Pharmacy
Practice at Brighton quickly grabbed attention when he revealed that
£2 billion of UK health resources is wasted per year due to
unused medication. This is occasioned by a 30-50% non-compliance rate
with most patients being non-compliant some of the time.
Psychological research has shown that patients form their own 'common
sense' models of their illness and evaluate health advice in a
'risk-benefit' analysis before responding to recommended treatment.
In a significant number of patients, beliefs that medicines were
oversubscribed or were essentially harmful and addictive presented
barriers to taking medication. Thus non-compliance may be a logical
attempt to moderate the perceived risks by taking less. Compliance
may be improved if patient and doctor engage in a more open dialogue
about the nature of the illness and treatment to lower 'motivational
barriers' alongside making the regime simple and convenient to
follow.

Professor Peter Redfern from the School of Pharmacy and
Pharmacology at Bath returned to the subject of chronotherapy - the
influence of time of day on drug response - with a talk on circadian
rhythms (CR) in physiological processes. Rhythms in blood pressure,
temperature, and hepatic metabolism for example respond both to the
biological clock residing in the suprachiasmatic nuclei of the
hypothalmus and the 24 hour day-night pattern of the environment.
Circadian periodicity can influence the 1) symptomatology of the
disease process over 24 hours 2) the pharmacokinetics of drugs (eg
due to the variations in physiological processes responsible for
absorption) 3) altered afficacy. Thus we should aim to deliver drugs
such as cytotoxic agents according to the rhythmic variation in
biological processes (the principles of chronotherapeutics).
Difficulties in applying this strategy include a deficiency of
knowledge of circadian periodicity in physiological processes, an
often small amplitude of the CR, significant inter-individual
variation and alteration of the normal CR by disease. A major
challenge to drug delivery technology lies in provision of a delivery
profile which varies reliably and reproducibly over 24 hours.

Lunch provided attendees with the opportunity to view the poster
exhibition, renew aquaintances and establish new contacts. Nineteen
posters were submitted all being automatically entered in the
competition for two prizes of £500 which are awarded annually to
the winning post graduate students to help attend the CRS
international meeting.

The first talk of the afternoon session was given by Professor
Philip Home of the Human Diabetes Research Institute, University of
Newcastle on the subject of 'Restoring Physiological Insulin
Delivery'. Professor Horne's first salient point was that insulin is
still injected 75 years after its discovery. A tendency for the
peptide to hexamerise, its acid solubility and surface adsorption
coupled with a widely varying physiological requirement, slow and
erratic absorption from the subcutaneous site and poor
bioavailability (insulin has a half-life of approximately 5 minutes
in the circulation) underline the challenges inherent in delivering
insulin effectively. Control of insulin delivery via glucose sensors
is desirable but indwelling sensors present biocompatibility
problems. Implanted insulin pumps have suffered from long-term
incompatibility of insulin with pump surfaces. Promising advances
have however been achieved in design of insulin molecules to prevent
hexamer formation and improve absorption rate or to prolong
absorption time to mimic basal insulin delivery between meals. Not
surprisingly, Professor Horne's specification of an ideal insulin
delivery device : diameter 10µm, 107 per person, multiple
inputs, fast response, no calibration, lifespan 70 years, powered by
the measured (glucose) molecule fitted the Islet B-cells of the
pancreas and turned attention once more to the potential of cell
encapsulation technology.

Dr David Chaplin from the Gray Laboratory, Cancer Research Trust
described the opportunities for targeting tumour epithelium so as to
cause shut-down of the tumour vascular function leading to secondary
tumour cell death. Significant selectivity between tumour and normal
tissue response is the key to effective targeting. Combretastatin
(A-4 disodium phosphate) was found to cause vascular shut-down at
1/10 the maximum tolerated dose and short in vitro drug exposure
resulted in long-term anti-proliferative/cytotoxic effects against
proliferating but not quiescent endothelial cells. The potency of
combretastatin A-4 was convincingly illustrated by an impressive
video recording of progressive vascular shut-down and tumour necrosis
in vivo in experimental models.

The coffee break provided valuable extra minutes for Dr Friederick
Rudenbekke to reach the lecture theatre after flying in from Germany
as a late replacement for Dr DeGrande of 3M. The talk on novel
transmucosal (TMD) and buccal drug delivery systems centred on the
advantages of 3Ms 'Cydot' adhesive patch devices which are positioned
on the gingiva of the gum. The system has been used to deliver
melatonine, buprenorphine and low Mw heparin and can provide rapid or
sustained delivery, good dose response and reproducibility. Other
advantages include low inter-subject variability and avoidance of
first pass liver metabolism. An intriguing future prospect raised by
Dr Rudenbekke involved TMD of therapeutic proteins and peptides.

The scientific session was brought to a close by Dr Glynn Wilson
of Access Pharmaceuticals who described some of the challenges facing
the development of novel polymer therapeutics. In particular, polymer
conjugates as pro-drugs or as components of particulate systems had
been shown to provide a number of opportunities for improving drug
efficacy by exploiting disease-related physiological changes (eg
'leaky' tumour endothelium) and specific drug release mechanisms.
However the successful translation of innovative research into
commercial products necessitated integration of basic research with
essential development activities. These included detailed safety
assessments, patent protection, pre-clinical and clinical testing and
education of industry and clinicians.

An extremely interesting meeting, notable for the high level of
audience participation through enthusiastic questioning of the
speakers, was closed by Professor Wilson. The two winners of the
£500 prizes for best posters were Aminul Islam from the Dept. of
Pharmaceutical and Biological Sciences at Aston for 'Studies on
uptake and sub-cellular trafficking of antisense
oligodeoxynucleotides using self assembling cationic lipids as
delivery systems' and Alison Potts from the Dept. Of Pharmaceutical
Sciences, University of Strathclyde for ' In vivo determination of
the oesophageal retention of smart hydrogels'.

It remains for the chairman and committee members of UK-Ireland
CRS to wish Aminul and Alison bon voyage and good luck in Vegas!